PPARα and GR Differentially Down-Regulate the Expression of Nuclear Factor-κB-Responsive Genes in Vascular Endothelial Cells

Abstract

The antiinflammatory action of glucocorticoids is mediated partly by the inhibition of the expression of several cytokines and adhesion molecules. Some activators for nuclear receptors other than the GR have also been shown to inhibit the expression of these inflammatory molecules, although their molecular mechanisms remain unidentified. We therefore examined the effects of the PPARalpha activator fenofibrate and the GR activator dexamethasone on TNFalpha-stimulated expression of IL-6 and vascular cell adhesion molecule-1 in vascular endothelial cells. Both fenofibrate and dexamethasone reduced TNFalpha-induced IL-6 production in human vascular endothelial cells, but only fenofibrate reduced TNFalpha-stimulated vascular cell adhesion molecule-1 expression in these cells. Transient transfection of bovine aortic endothelial cells with an IL-6 promoter construct or a vascular cell adhesion molecule-1 promoter construct revealed that fenofibrate inhibited TNFalpha-induced IL-6 promoter as well as vascular cell adhesion molecule-1 promoter activities, whereas dexamethasone inhibited only the former. EMSA demonstrated that both fenofibrate and dexamethasone reduced nuclear factor-kappaB binding to its recognition site on the IL-6 promoter, but only fenofibrate reduced such binding to the vascular cell adhesion molecule-1 promoter. Thus, down-regulation of nuclear factor-kappaB activity by PPARalpha occurs in both the IL-6 and vascular cell adhesion molecule-1 genes, whereas that by GR occurs only in the IL-6 gene in vascular endothelial cells. These results strongly suggest the existence of a target gene-specific mechanism for the nuclear receptor-mediated down-regulation of nuclear factor-kappaB activity.

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“…Consequently, glitazones like troglitazone should reduce the expression of both cytokines and ECAMs driven by NF-kB [6,41,57]. Interestingly, under control culture conditions, we observe basal phosphorylation of p65, suggesting that normally, p65 is at least partially activated.…”

“…Troglitazone significantly reduced TNF-α induced expression of several other ECAMs as well [6,21,30,32,38,41,57], and decreased the adhesion of α4β7-expressing lymphocytes (TK-1) to TNF-α stimulated endothelium. Since at least 50% of the adhesion of these lymphocytes to TNF-stimulated endothelium is MAdCAM-1-dependent [35], our results suggest that MAdCAM-1 mediates most of the stimulated adhesion, with more minor contributions from other ECAMs.…”

The Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-α–Dependent Manner In Vitro and In Vivo in Mice

“…Circulating levels of VCAM-1 may predict subsequent clinical cardiovascular events (62) while VCAM-1 may be elevated in T2DM, perhaps as a result of the hypertriglyceridemia and/or low HDL-C (34,63,64). Reducing TG levels with fibrates or fish oil, both of which can be considered PPARα activators (67,68), reportedly decrease soluble adhesion molecule levels (32,65,66). VCAM-1 expression is controlled by multiple pathways, including NF-κB and PPARα (69).…”

Peroxisome proliferator‐activated receptors – from active regulators of macrophage biology to pharmacological targets in the treatment of cardiovascular disease

“…Experimental data provide evidences that the three PPAR isotypes modulate monocyte recruitment and retention. Indeed, activated PPARα inhibits cytokine‐induced expression of ICAM‐1 and VCAM‐1 in EC [19, 20] and PPARβ/δ activation results in decreased expression of MCP‐1 and ICAM‐1 in the aorta of treated LDL‐receptor (LDLR) −/− mice, an experimental model of atherosclerosis [21]. PPARγ is also involved in monocyte adhesion and transmigration.…”